T cells & IL-17

Role of T Cells in Lung Ischemia-Reperfusion Injury

Despite refinements in lung
preservation and improvements in surgical technique and perioperative
care, IR injury remains a significant cause of early morbidity and
mortality after lung transplant. Clearly, prevention of IR injury is
sorely needed.

We are utilizing both in vivo and in vitro models as complementary
approaches to study mechanisms of lung IR injury. We have demonstrated
a vital role for alveolar macrophages and TNF-alpha production in lung IR
injury and have described crosstalk between macrophages and alveolar
epithelial cells during IR injury. Current studies are focused on
evaluating the role of CD4+ T cells, T cell-derived cytokines, and the
innate immune system in lung IR injury. Preliminary studies indicate
that NKT cells are pivotal for the initiation of IR injury and that NKT
cell-produced IL-17 is a key chemokine for the activation and
infiltration of neutrophils which lead to tissue damage. Dendritic
cell-derived IL-23 also seems to be an upstream mediator of NKT cell
activation. In addition, oxidative stress mechanisms of IR injury are
being studied. Here, NADPH oxidase-generated reactive oxygen
species is a key component of immune cell activation upon
reperfusion, and we are studying the role of NADPH oxidase in
various cell types in mediating IR-induced inflammatory pathways. Our
laboratory uses various knockout and chimeric mice, immune cell
ablation studies with diphtheria toxin in susceptible transgenic mice,
adoptive transfer studies, and cultured immune cells to address
mechanistic questions both in vivo and in vitro to study mechanisms of
lung IR injury. In testing our hypotheses we hope to gain further
knowledge of the pathways that mediate lung IR injury that will enable
the development of specific small molecules that can be used in future
clinical studies.

Representative flow cytometric analysis of IL-17-expressing
leukocytes. Wild-type mice underwent either sham or IR surgery, and
cell suspensions were prepared from left lungs. CD45+
7-AAD- B220- TCRb+ cells were gated
and further assessed by flow cytometry as shown. The numbers within
each box indicate the percentage of cells gated. (A) The number
of IL-17-expressing iNKT cells (IL-17+ CD1d
tetramer+) was increased after IR compared to sham.
(B) A substantial increase in the number of IL-17-expressing
neutrophils (IL-17+ Gr-1+) occurred after IR.
(C) The number of IL-17-expressing gd T cells (IL-17+
gdTCR+) was not increased after IR compared to sham.